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A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer

This study has been terminated.
(Enrollment to the study was terminated on 11Nvo2014 due to slow recruitment. There were no safety or efficacy issues that contributed to this decision.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01925274
First received: August 15, 2013
Last updated: April 28, 2017
Last verified: April 2017
  Purpose
This study will investigate whether the combination of PF-05212384 plus Irinotecan improves progression free survival in patients with KRAS and NRAS wild type metastatic colorectal cancer when compared with the combination of cetuximab plus Irinotecan. A Japanese Lead in Cohort will assess the safety of the combination of PF-05212384 + irinotecan in patients enrolled at Japanese sites.

Condition Intervention Phase
Metastatic Colorectal Cancer Drug: PF-05212384 Drug: irinotecan Drug: Cetuximab Drug: Irinotecan Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Randomized Phase 2 Study Of Pf-05212384 Plus Irinotecan Versus Cetuximab Plus Irinotecan In Patients With Kras And Nras Wild Type Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Progression Free Survival (PFS) as Assessed by Investigators [ Time Frame: From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years ]
    Progression-free survival (PFS) was the time from the first dose of study treatment to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. Median PFS was estimated based on the Kaplan-Meier method.


Secondary Outcome Measures:
  • Number of Participants With Unacceptable Toxicity in Cycle 1 (Japanese LIC Only) [ Time Frame: 28 days ]
    Unacceptable toxicity (according to Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0) was any of the following occurrences: (1) Grade 4 neutropenia >7 days, or febrile neutropenia, or Grade 4 thrombocytopenia; (2) Grade >=3 nausea/vomiting despite optimal antiemetic treatment, or Grade >=3 diarrhea despite optimal anti diarrheal treatment; (3) unmanageable Grade >=3 hyperglycemia; (4) mean QTc interval (time from electrocardiogram [ECG] Q wave to the end of the T wave corresponding to electrical systole, corrected for heart rate) >501 msec in triplicate 12-lead ECG, or myocardial infarction, or ventricular arrhythmia; (5) Grade >=3 non-hematologic toxicity; (6) treatment delay of >=2 weeks due to study drug related toxicity; (7) persistent, intolerable toxicities which resulted in failure to deliver at least 75% of doses of both PF-05212384 and irinotecan during Cycle 1; (8) Grade >=2 respiratory toxicities.

  • Percentage of Participants With Objective Response [ Time Frame: 2 years ]
    Percentage of participants with objective response was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Confirmed PR was defined as disappearance of all target lesions. Confirmed PR was defined as >=30% decrease in sum of the longest dimensions of the target lesions taking the baseline sum as a reference. Confirmed responses were those that persisted on repeat imaging study >=4 weeks after initial documentation of response.

  • Duration of Response [ Time Frame: 2 years ]
    For participants with an objective response (CR or PR), duration of response was defined as the time from first documentation of CR or PR to date of first documentation of objective progression or death. Date of first documentation of progression and date of first documentation of CR or PR were based on Investigator's assessment of response.

  • Overall Survival (OS) [ Time Frame: 2 years ]
    Overall survival (OS) was defined as the duration from enrollment to death. Participants last known to be alive were censored at date of last contact.

  • Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Administration of the first dose of study drug through 28 calendar days after the last administration of study drug ]
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE was defined as any untoward occurrence at any dose that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug.

  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Common Terminology Criteria for Adverse Events (CTCAE) Grade [ Time Frame: Administration of the first dose of study drug through 28 calendar days after the last administration of study drug ]
    TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. CTCAE version 4.0 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE.

  • Number of Participants With Laboratory Test (Hematology) Abnormalities [ Time Frame: 2 years ]
    The following hematology parameters were evaluated in this study: hemoglobin, white blood cells (WBC) with differential, and platelets.

  • Number of Participants With Laboratory Test (Chemistry) Abnormalities [ Time Frame: 2 years ]
    The following chemistry parameters were evaluated in this study: sodium, potassium, magnesium, chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, blood urea nitrogen (BUN) or urea, creatinine, total calcium, glycosylated hemoglobin (HbA1c), glucose, uric acid, phosphorus or phosphate, insulin, and C-peptide.

  • Number of Participants With Laboratory Test (Urinalysis) Abnormalities [ Time Frame: 2 years ]
    Urinalysis included urine dipstick for protein and blood: if positive, perform a microscopic analysis. Number of participants with urine protein tested positive is presented.

  • Number of Participants With Laboratory Test (Coagulation) Abnormalities [ Time Frame: 2 years ]
    Coagulation analysis included partial thromboplastin time (PTT) and international normalized ratio (INR) or prothrombin time (PT).

  • Number of Participants With ECG Post-Baseline Maximum Absolute Values Meeting Pre-defined Criteria [ Time Frame: 2 years ]
    The number of participants with ECG post-baseline maximum absolute values meeting the following criteria was reported: (1) maximum QTc interval ranged from 450 to 480 msec; >480-500 msec; >500 msec; (2) maximum QTcB (QT corrected for heart rate using Bazett's formula) interval ranged from 450 to 480 msec; >480-500 msec; >500 msec; (3) maximum QTcF (QT corrected for heart rate using Fridericia's formula) interval ranged from 450 to 480 msec; >480-500 msec; >500 msec.

  • Number of Participants With ECG Maximum Increase From Baseline Meeting Pre-defined Criteria [ Time Frame: 2 years ]

    The number of participants with ECG maximum increase from baseline meeting the following criteria was reported:

    Criterion A: maximum QTc interval increase from baseline >30 msec and ≤60 msec; criterion B: maximum QTc interval increase from baseline >60 msec; criterion C: maximum QTcB interval increase from baseline >30 msec and ≤60 msec; criterion D: maximum QTcB interval increase from baseline >60 msec; criterion E: maximum QTcF interval increase from baseline >30 msec and ≤60 msec; criterion F: maximum QTcF interval increase from baseline >60 msec.


  • Maximum Plasma Concentration (Cmax) of PF-05212384 [ Time Frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. ]
    Cmax of PF-05212384 was observed directly from data.

  • Maximum Plasma Concentration (Cmax) of Irinotecan [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    Cmax of irinotecan was observed directly from data.

  • Maximum Plasma Concentration (Cmax) of SN-38 [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    SN-38 is an irinotecan metabolite. Cmax of SN-38 was observed directly from data.

  • Time for Maximum Plasma Concentration (Tmax) of PF-05212384 [ Time Frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. ]
    Tmax of PF-05212384 was observed directly from data as time of first occurrence.

  • Time for Maximum Plasma Concentration (Tmax) of Irinotecan [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    Tmax of irinotecan was observed directly from data as time of first occurrence.

  • Time for Maximum Plasma Concentration (Tmax) of SN-38 [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    SN-38 is an irinotecan metabolite. Tmax of SN-38 was observed directly from data as time of first occurrence.

  • Terminal Elimination Half Life (t½) of PF-05212384 [ Time Frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9 and Cycle 1 Day 16. ]
    T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

  • Terminal Elimination Half Life (t½) of Irinotecan [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

  • Terminal Elimination Half Life (t½) of SN-38 [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    T½ was calculated as loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.

  • Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of PF-05212384 [ Time Frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9. ]
    AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of PF-05212384 was determined using linear/log trapezoidal method.

  • Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of Irinotecan [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of irinotecan was determined using linear/log trapezoidal method.

  • Area Under Plasma Concentration Time Profile From Time Zero to the Time for the Last Quantifiable Concentration (AUClast) of SN-38 [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    AUClast refers to the area under plasma concentration time profile from time zero to the time for the last quantifiable concentration. AUClast of SN-38 (an irinotecan metabolite) was determined using linear/log trapezoidal method.

  • Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-05212384 [ Time Frame: Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 24, 72, 120 hours post PF-05212384 infusion on Cycle 1 Day 9. ]
    AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of PF-05212384 was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.

  • Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Irinotecan [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of irinotecan was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.

  • Area Under Plasma Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of SN-38 [ Time Frame: Pre-dose (0 hour), 1.5, 2, 4, 6 and 24 hours post irinotecan infusion on Cycle 1 Day 1 and Cycle 2 Day 1. ]
    AUCinf refers to the area under plasma concentration time profile from time zero extrapolated to infinite time. AUCinf of SN-38 (an irinotecan metabolite) was calculated using the formula: AUCinf = AUClast + (Clast*/kel), where Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.

  • Levels of Signaling Proteins in Paired and Single Tumor Biopsies [ Time Frame: 2 years ]
    Pre defined signaling proteins included Akt (protein kinase B), p-Akt (phosphorylated Akt), p-S6 (phosphorylated ribosomal protein S6), p-Met (phosphorylated Met, a receptor tyrosine kinase), p-mTOR (phosphorylated mammalian target of rapamycin), EGFR (epithelial growth factor receptor), and p-EGFR (phosphorylated EGFR).

  • Number of Participants With Expression of Pre-defined Gene Sequences in Biopsied Tumor Tissues [ Time Frame: 2 years ]
    Pre-defined gene sequences were those related to EGFR, PI3K (phosphoinositide-3 kinase) and other oncogenic pathways; examples included but were not limited to PIK3CA (this gene encodes the catalytic subunit of PI3K), PIK3R1 (this gene encodes the regulatory subunit of PI3K), KRAS, NRAS and BRAF (this gene encodes serine/threonine-protein kinase B-Raf) sequences and PIK3CA gene amplification. Due to early termination of this study, these pre-defined gene sequences were not analyzed, except for KRAS and NRAS. Number of participants who had KRAS and NRAS wild type status confirmed by the central laboratory is presented.

  • Change From Baseline in Functional Assessment of Cancer Therapy-Colorectal (FACT-C) [ Time Frame: 2 years ]
    Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was used in this study to assess Health-Related Quality of Life (HRQoL) and CRC-related symptoms in participants enrolled to the randomized portion of the study. The FACT-C is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, a comprehensive and extensive set of self-reported instruments for the assessment of health-related quality of life in participants with cancer or other chronic illnesses.


Enrollment: 19
Study Start Date: November 2013
Study Completion Date: April 2016
Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
PF-05212384 plus Irinotecan
Drug: PF-05212384
30 minute IV infusion of PF-05212384 on days 2, 9, 16 and 23 of each cycle. Intra-patient dose escalation will commence with 110mg and will increase depending on tolerability.
Other Name: PKI-587
Drug: irinotecan
90 minutes IV infusion of irinotecan 180mg/m^2 on days 1 and 15 of each cycle
Other Name: Camptosar, Campto, CPT-11
Active Comparator: Arm B
Cetuximab plus Irinotecan
Drug: Cetuximab
120 minute IV infusion of cetuximab 400mg/m^2 on cycle 1 day 1; 60 minute IV infusion of cetuximab on days 8, 15, and 22 of each cycle, and on day 1 of each cycle after cycle 1
Other Name: Erbitux
Drug: Irinotecan
90 minutes IV infusion of Irinotecan 180mg/m^2 on days 1 and 15 of each cycle
Other Name: Camptosar, Campto, CPT-11

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • KRAS and NRAS wild type metastatic colorectal cancer
  • Progression following treatment for colorectal cancer with irinotecan, oxaliplatin and fluoropyrimidine therapy in the metastatic setting.
  • Eastern Cooperative Oncology Group [ECOG] Performance Status of 0, 1, or 2
  • At least one measurable lesion by Response Evaluation Criterion in Solid Tumors [RECIST]

Exclusion Criteria:

  • More than 2 prior cytotoxic chemotherapy regimens for metastatic colorectal cancer.
  • Prior treatment with a PI3K, mTOR, AKT or EGFR inhibitor
  • Patients who have discontinued treatment with prior irinotecan therapy due to toxicity.
  • Prior radiation to the pelvis or abdomen
  • Patients with history of interstitial lung disease.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01925274

Locations
United States, California
CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center
Bakersfield, California, United States, 93309
Drug Management Only: UCLA West Medical Pharmacy, Att: Steven L Wong, Pharm D
Los Angeles, California, United States, 90095-7349
Drug Management Only: UCLA West Medical Pharmacy
Los Angeles, California, United States, 90095-7349
UCLA West Medical Pharmacy
Los Angeles, California, United States, 90095-7349
Regulatory Management Only: TRIO-US Central Administration
Los Angeles, California, United States, 90095
TRIO-US Central Administration (Regulatory Management only)
Los Angeles, California, United States, 90095
TRIO_US
Los Angeles, California, United States, 90095
West Valley Hematology/Oncology Med Group
Northridge, California, United States, 91328
United States, Missouri
Siteman Cancer Center - West County
Creve Coeur, Missouri, United States, 63141
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63110
Drug Shipping Address: Washington University Infusion Center Pharmacy
Saint Louis, Missouri, United States, 63110
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Siteman Cancer Center - South County
Saint Louis, Missouri, United States, 63129
Siteman Cancer Center - St Peters
Saint Peters, Missouri, United States, 63376
United States, Nevada
Regulatory Office: Comprehensive Cancer Centers of Nevada
Henderson, Nevada, United States, 89014
Comprehensive Cancer Centers of Nevada
Henderson, Nevada, United States, 89052
Comprehensive Cancer Centers of Nevada
Henderson, Nevada, United States, 89074
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States, 89128
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States, 89148
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States, 89169
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Washington
Kadlec Clinic Hematology and Oncology
Kennewick, Washington, United States, 99336
Kadlec Medical Center
Richland, Washington, United States, 99352
Outpatient Imaging Center
Richland, Washington, United States, 99352
Spokane Valley Cancer Center
Spokane Valley, Washington, United States, 99216
Medical Oncology Associates, PS
Spokane, Washington, United States, 99208
Japan
Aichi cancer center central hospital
Nagoya, Aichi, Japan, 464-8681
National Cancer Center Hospital East
Kashiwa, Chiba, Japan, 277-8577
Korea, Republic of
National Cancer Center
Goyang-si, Gyeonggi-do, Korea, Republic of, 410-769
Seoul National University Hospital / Department of Internal Medicine
Seoul, Korea, Republic of, 110-744
Samsung Medical Center
Seoul, Korea, Republic of, 135-710
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Spain
Hospital General Universitario Gregorio Marañón
Madrid, Spain, 28009
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01925274     History of Changes
Other Study ID Numbers: B2151005
2013-002095-40 ( EudraCT Number )
Study First Received: August 15, 2013
Results First Received: January 9, 2017
Last Updated: April 28, 2017

Keywords provided by Pfizer:
metastatic colorectal cancer
colorectal cancer
KRAS
colon cancer
mCRC
CRC
PF-05212384
KRAS wild type colorectal cancer
irinotecan
cetuximab
NRAS

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Camptothecin
Cetuximab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 23, 2017